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首页> 外文期刊>Glia >GABAergic Disinhibition and Impaired KCC2 Cotransporter Activity Underlie Tumor-Associated Epilepsy
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GABAergic Disinhibition and Impaired KCC2 Cotransporter Activity Underlie Tumor-Associated Epilepsy

机译：GABA能抑制作用和KCC2转运蛋白活性受损是肿瘤相关性癫痫的基础

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Seizures frequently accompany gliomas and often escalate to peritumoral epilepsy. Previous work revealed the importance of tumor-derived excitatory glutamate (Glu) release mediated by the cystine-glutamate transporter (SXC) in epileptogenesis. We now show a novel contribution of GABAergic disinhibition to disease pathophysiology. In a validated mouse glioma model, we found that peritumoral parvalbumin-positive GABAergic inhibitory interneurons are significantly reduced, corresponding with deficits in spontaneous and evoked inhibitory neurotransmission. Most remaining peritumoral neurons exhibit elevated intracellular Cl- concentration ([Cl-](i)) and consequently depolarizing, excitatory gamma-aminobutyric acid (GABA) responses. In these neurons, the plasmalemmal expression of KCC2, which establishes the low [Cl-](i) required for GABA(A)R-mediated inhibition, is significantly decreased. Interestingly, reductions in inhibition are independent of Glu release, but the presence of both decreased inhibition and decreased SXC expression is required for epileptogenesis. We suggest GABAergic disinhibition renders peritumoral neuronal networks hyper-excitable and susceptible to seizures triggered by excitatory stimuli, and propose KCC2 as a therapeutic target. GLIA 2015;63:23-36
机译：癫痫发作通常伴随神经胶质瘤，并且经常升级为肿瘤周围性癫痫。先前的工作揭示了由胱氨酸-谷氨酸转运蛋白（SXC）介导的肿瘤来源的兴奋性谷氨酸（Glu）释放在癫痫发生中的重要性。我们现在显示GABA能抑制作用对疾病病理生理的新贡献。在一个经过验证的小鼠神经胶质瘤模型中，我们发现肿瘤周围小白蛋白阳性的GABAergic抑制性中间神经元显着减少，这与自发和诱发的抑制性神经传递不足有关。其余大多数肿瘤周围神经元表现出升高的细胞内Cl浓度（[Cl-]（i）），因此去极化，兴奋性γ-氨基丁酸（GABA）反应。在这些神经元中，建立GABA（A）R介导的抑制所需的低[Cl-]（i）的KCC2的血浆表达明显降低。有趣的是，抑制的减少与Glu的释放无关，但是抑制作用的降低和SXC表达的降低是癫痫发生所必需的。我们建议GABA能抑制作用使肿瘤周围神经元网络高度兴奋，并容易受到兴奋性刺激触发的癫痫发作，并建议将KCC2作为治疗靶点。 GLIA 2015; 63：23-36

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